Context The metabolic syndrome has been identified as a target for dietary therapies to reduce risk of cardiovascular disease; however, the role of diet in the etiology of the metabolic syndrome is poorly understood. Objective To assess the effect of a Mediterranean-style diet on endothelial function and vascular inflammatory markers in patients with the metabolic syndrome. Design, Setting, and Patients Randomized, single-blind trial conducted from June 2001 to January 2004 at a university hospital in Italy among 180 patients (99 men and 81 women) with the metabolic syndrome, as defined by the Adult Treatment Panel III. Interventions Patients in the intervention group (n=90) were instructed to follow a Mediterranean-style diet and received detailed advice about how to increase daily consumption of whole grains, fruits, vegetables, nuts, and olive oil; patients in the control group (n=90) followed a prudent diet (carbohydrates, 50%-60%; proteins, 15%-20%; total fat, <30%). Main Outcome Measures Nutrient intake; endothelial function score as a measure of blood pressure and platelet aggregation response to L-arginine; lipid and glucose parameters; insulin sensitivity; and circulating levels of high-sensitivity C-reactive protein (hs-CRP) and interleukins 6 (IL-6), 7 (IL-7), and 18 (IL-18). Results After 2 years, patients following the Mediterranean-style diet consumed more foods rich in monounsaturated fat, polyunsaturated fat, and fiber and had a lower ratio of omega-6 to omega-3 fatty acids. Total fruit, vegetable, and nuts intake (274 g/d), whole grain intake (103 g/d), and olive oil consumption (8 g/d) were also significantly higher in the intervention group (P<.001). The level of physical activity increased in both groups by approximately 60%, without difference between groups (P=.22). Mean (SD) body weight decreased more in patients in the intervention group (−4.0 [1.1] kg) than in those in the control group (−1.2 [0.6] kg) (P<.001). Compared with patients consuming the control diet, patients consuming the intervention diet had significantly reduced serum concentrations of hs-CRP (P=.01), IL-6 (P=.04), IL-7 (P=0.4), and IL-18 (P=0.3), as well as decreased insulin resistance (P<.001). Endothelial function score improved in the intervention group (mean [SD] change, +1.9 [0.6]; P<.001) but remained stable in the control group (+0.2 [0.2]; P=.33). At 2 years of follow-up, 40 patients in the intervention group still had features of the metabolic syndrome, compared with 78 patients in the control group (P<.001). Conclusion A Mediterranean-style diet might be effective in reducing the prevalence of the metabolic syndrome and its associated cardiovascular risk.